Methods of treating and preventing pain, anxiety, and incontinence using derivatives of (-)-venlafaxine

ABSTRACT

Methods of preparing, and compositions comprising, derivatives of (−)-venlafaxine are disclosed. Also disclosed are methods of treating and preventing diseases and disorders including, but not limited to, affective disorders such as depression, bipolar and manic disorders, attention deficit disorder, attention deficit disorder with hyperactivity, Parkinson&#39;s disease, epilepsy, cerebral function disorders, obesity and weight gain, incontinence, dementia and related disorders.

1. FIELD OF INVENTION

[0001] The invention relates to optically pure derivatives of(-)-venlafaxine, methods of their synthesis, compositions comprisingthem, and methods of their use.

2. BACKGROUND OF THE INVENTION

[0002] A number of nontricyclic antidepressants have recently beendeveloped that diminish the cardiovascular and anticholinergic liabilitycharacteristic of tricyclic antidepressants. Some of these compounds areused as anti-obesity agents and have shown promise in the treatment ofcerebral function disorders such as Parkinson's disease and seniledementia. See, e.g., WO 94/00047 and WO 94/00114. The nontricycliccompound venlafaxine, chemically named(±)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol, is anantidepressant which has been studied extensively and which is describedin, for example, U.S. Pat. No. 4,761,501 and Pento, J. T. Drugs of theFuture 13(9):839-840 (1988). Its hydrochloride salt is currentlycommercially available in the United States under the trade nameEffexor®. Effexor®, which is a racemic mixture of the (+) and (−)enantiomers of venlafaxine, is indicated for the treatment ofdepression.

[0003] Although venlafaxine contains an asymmetric carbon atom and issold as a racemate, it has been reported that its (−) enantiomer is amore potent inhibitor of norepinephrine synaptosomal uptake while its(+) enantiomer is more selective in inhibiting serotonin uptake. Howell,S. R. et al. Xenobiotica 24(4):315-327 (1994). Furthermore, studies haveshown that the ratio of the two isomers' metabolism varies not onlyamong species, but between subjects as well. Klamerus, K. J. et al. J.Clin. Pharmacol. 32:716-724 (1992). In humans, venlafaxine istransformed by a saturable metabolic pathway into two minor metabolites,N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine, and one majormetabolite, O-desmethylvenlafaxine, as shown in Scheme I(a):

[0004] Klamerus, K. J. et al. J. Clin. Pharmacol. 32:716-724 (1992). Allof these metabolites are racemic. In vitro studies suggest thatO-desmethylvenlafaxine is a more potent inhibitor of norepinephrine anddopamine uptake than the parent compound racemic venlafaxine. Muth, E.A. et al. Drug Develop. Res. 23:191-199 (1991). O-desmethylvenlafaxinehas also been reported to have a half-life (t½) of about 10 hours, whichis approximately 2.5 times as long as that of venlafaxine. Klamerus, K.J. et al. J. Clin. Pharmacol. 32:716-724 (1992). Studies directed atunderstanding the activity of O-desmethylvenlafaxine as compared to itsparent have been hampered, however, by the metabolic difference betweenlaboratory animals and man in their exposure to venlafaxine. Howell, S.R. et al. Xenobiotica 24(4):315-327 (1994).

[0005] Despite the benefits of racemic venlafaxine, it has adverseeffects including, but not limited to, sustained hypertension, headache,asthenia, sweating, nausea, constipation, somnolence, dry mouth,dizziness, insomnia, nervousness, anxiety, blurred or blurry vision, andabnormal ejaculation/orgasm or impotence in males. Physicians' DeskReference pp. 3293-3302 (53^(rd) ed., 1999); see also Sinclair, J. etal. Rev. Contemp. Pharmacother. 9:333-344 (1998). These adverse effectscan significantly limit the dose level, frequency, and duration of drugtherapy. It would thus be desirable to find a compound with theadvantages of venlafaxine while avoiding its disadvantages.

3. SUMMARY OF THE INVENTION

[0006] This invention relates to novel pharmaceutical compositionscomprising optically pure derivatives of (−)-venlafaxine such as(−)-O-desmethylvenlafaxine. The invention also relates to methods ofpreparing optically pure derivatives of (−)-venlafaxine with high purityand in high yield, and to methods of treating and preventing diseasesand disorders which comprise the administration of one or more opticallypure derivatives of (−)-venlafaxine to a human in need of such treatmentor prevention.

[0007] Methods and compositions of the invention can be used to treat orprevent depression and affective disorders such as, but not limited to,attention deficit disorder and attention deficit disorder withhyperactivity. Methods and compositions of the invention are also usefulin treating obesity and weight gain in a human. The invention alsoencompasses the treatment of cerebral function disorders including, butnot limited to, senile dementia, Parkinson's disease, epilepsy,Alzheimer's disease, amnesia/amnestic syndrome, autism andschizophrenia; disorders ameliorated by inhibition of neuronal monaminereuptake; and pain, particularly chronic pain. The invention furtherencompasses the treatment or prevention of obsessive-compulsivedisorder, substance abuse, pre-menstrual syndrome, anxiety, eatingdisorders and migraines. The invention finally encompasses the treatmentor prevention of incontinence in humans.

[0008] The compounds and compositions of the invention possess potentactivity for treating or preventing the above-described disorders whilereducing or avoiding adverse effects including, but not limited to,sustained hypertension, headache, asthenia, sweating, nausea,constipation, somnolence, dry mouth, dizziness, insomnia, nervousness,anxiety, blurred or blurry vision, and abnormal ejaculation/orgasm orimpotence in males. In particular, adverse effects associated with theadministration of racemic venlafaxine are reduced or avoided by the useof optically pure derivatives of (−)-venlafaxine. Compositions of theinvention can also exhibit long half lives as compared to racemicvenlafaxine.

[0009] Although a variety of pharmaceutical salts, solvates, clatheratesand/or hydrates (including anhydrous forms) of the active ingredientsdisclosed herein are suitable for use in the methods and compositions ofthe invention, the optically pure derivatives of (−)-venlafaxine aretypically prepared as hydrochloride salts, and preferably as themonohydrates.

3.1. DEFINITIONS

[0010] As used herein, the term “venlafaxine” means the racemic compound(±)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol.

[0011] As used herein, the tens “venlafaxine derivative” and “derivativeof venlafaxine” encompass, but are not limited to, human metabolites ofracemic venlafaxine. In particular, the terms “venlafaxine derivative”and “derivative of venlafaxine” mean a compound selected from the groupthat includes, but is not limited to: (±)-N-desmethylvenlafaxine,chemically named(±)-1-[2-(methylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol;(±)-N,N-didesmethylvenlafaxine, chemically named(1)-i-[2-(amino)-1-(4-methoxyphenyl)ethyl]cyclohexanol;(±)-O-desmethylvenlafaxine, chemically named(+)-1-[2-(dimethylamino)-1-(4-phenol)ethyl]cyclohexanol;(+)-N,O-didesmethylvenlafaxine, chemically named(+)-1-[2-(methylamino)-1-(4-phenol)ethyl]cyclohexanol; and(±)-O-desmethyl-N,N-didesmethylvenlafaxine, chemically named chemicallynamed (+)-1-[2-(amino)-1-(4-phenol)ethyl]cyclohexanol.

[0012] As used herein, the terms “(−)-venlafaxine derivative” and“derivative of (−)-venlafaxine” encompass, but are not limited to,optically pure human metabolites of (−)-venlafaxine. In particular, theterms “(−)-venlafaxine derivative” and “derivative of (−)-venlafaxine”mean a compound selected from the group that includes, but is notlimited to: optically pure (−)-N-desmethylvenlafaxine, chemically named(−)-1-[2-(methylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol; opticallypure (−)-N,N-didesmethylvenlafaxine, chemically named(−)-1-[2-(amino)-1-(4-methoxyphenyl)ethyl]cyclohexanol; optically pure(−)-O-desmethylvenlafaxine, chemically named(−)-1-[2-(dimethylamino)-1-(4-phenol)ethyl]cyclohexanol; optically pure(−)-N,O-didesmethylvenlafaxine, chemically named(−)-1-[2-(methylamino)-1-(4-phenol)ethyl]cyclohexanol; and opticallypure (−)-O-desmethyl-N,N-didesmethylvenlafaxine, chemically namedchemically named (−)-1-[2-(amino)-1-(4-phenol)ethyl]cyclohexanol.

[0013] As used herein, the terms “(+)-venlafaxine derivative” and“derivative of (+)-venlafaxine” encompass, but are not limited to,optically pure human metabolites of (+)-venlafaxine. In particular, theterms “(+)-venlafaxine derivative” and “derivative of (+)-venlafaxine”mean a compound selected from the group that includes, but is notlimited to: optically pure (+)-N-desmethylvenlafaxine, chemically named(+)-1-[2-(methylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol; opticallypure (+)-N,N-didesmethylvenlafaxine, chemically named(+)-1-[2-(amino)-1-(4-methoxyphenyl)ethyl]cyclohexanol; optically pure(+)-O-desmethylvenlafaxine, chemically named(+)-1-[2-(dimethylamino)-1-(4-phenol)ethyl]cyclohexanol; optically pure(+)-N,O-didesmethylvenlafaxine, chemically named(+)-1-[2-(methylamino)-1-(4-phenol)ethyl]cyclohexanol; and opticallypure (+)-O-desmethyl-N,N-didesmethylvenlafaxine, chemically namedchemically named (+)-1-[2-(amino)-1-(4-phenol)ethyl]cyclohexanol.

[0014] As used herein to describe a compound, the term “substantiallyfree of its (+) stereoisomer” means that the compound is made up of asignificantly greater proportion of its (−) stereoisomer than of itsoptical antipode (i.e., its (+) stereoisomer). In a preferred embodimentof the invention, the term “substantially free of its (+) stereoisomer”means that the compound is made up of at least about 90% by weight ofits (−) stereoisomer and about 10% by weight or less of its (+)stereoisomer. In a more preferred embodiment of the invention, the term“substantially free of its (+) stereoisomer” means that the compound ismade up of at least about 95% by weight of its (−) stereoisomer andabout 5% by weight or less of its (+) stereoisomer. In an even morepreferred embodiment, the term “substantially free of its (+)stereoisomer” means that the compound is made up of at least about 99%by weight of its (−) stereoisomer and about 1% or less of its (+)stereoisomer. In another preferred embodiment, the term “substantiallyfree of its (+) stereoisomer” means that the compound is made up ofnearly 100% by weight of its (−) stereoisomer. The above percentages arebased on the total amount of the combined stereoisomers of the compound.The terms “substantially optically pure (−)-venlafaxine derivative,”“optically pure (−)-venlafaxine derivative” and “(−) isomer ofvenlafaxine derivative” all refer to a derivative of (−)-venlafaxinethat is substantially free of its (+) stereoisomer.

[0015] As used herein, the term “pharmaceutically acceptable salts”refers to salts prepared from pharmaceutically acceptable non-toxicacids, including inorganic acids and organic acids. Suitable non-toxicacids include inorganic and organic acids such as acetic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric acid,p-toluenesulfonic and the like. Particularly preferred are hydrochloric,hydrobromic, phosphoric, and sulfuric acids, and most particularlypreferred is the hydrochloride salt.

[0016] As used herein, the term “affective disorder” includesdepression, attention deficit disorder, attention deficit disorder withhyperactivity, bipolar and manic conditions, and the like. The terms“attention deficit disorder” (ADD) and “attention deficit disorder withhyperactivity” (ADDH), or attention deficit/hyperactivity disorder(AD/HD), are used herein in accordance with the accepted meanings asfound in the Diagnostic and Statistical Manual of Mental Disorders,4^(th) Ed., American Psychiatric Association (1997) (DSM-IV™).

[0017] As used herein, the term “a method of treating depression” meansrelief from the symptoms of depression which include, but are notlimited to, changes in mood, feelings of intense sadness, despair,mental slowing, loss of concentration, pessimistic worry, agitation, andself-deprecation. Physical changes may also be relieved, includinginsomnia, anorexia, weight loss, decreased energy and libido, andabnormal hormonal circadian rhythms.

[0018] As used herein, the term “a method for treating obesity or weightgain” means reduction of weight, relief from being overweight, relieffrom gaining weight, or relief from obesity; all of which are usuallydue to extensive consumption of food.

[0019] As used herein, the term “a method of treating disordersameliorated by inhibition of neuronal monoamine reuptake” means relieffrom symptoms of disease states associated with abnormal neuronalmonoamine levels; such symptoms are reduced by way of neuronal monoaminereuptake inhibition. Monoamines, the reuptake of which are inhibited bythe compounds or compositions of the present invention, include, but arenot limited to, noradrenaline (or norepinephrine), serotonin anddopamine. Disorders treated by neuronal monoamine reuptake inhibitioninclude, but are not limited to, Parkinson's disease and epilepsy.

[0020] As used herein, the term “method of treating Parkinson's disease”means relief from the symptoms of Parkinson's disease which include, butare not limited to, slowly increasing disability in purposeful movement,tremors, bradykinesia, rigidity, and a disturbance of posture in humans.

[0021] As used herein, the term “a method for treating cerebral functiondisorders” means relief from the disease states associated with cerebralfunction disorders involving intellectual deficits which include but arenot limited to, senile dementia, Alzheimer's type dementia, memory loss,amnesia/amnestic syndrome, disturbances of consciousness, coma, loweringof attention, speech disorders, Parkinson's disease, Lennox syndrome,autism, hyperkinetic syndrome and schizophrenia. Also within the meaningof cerebral function disorders are disorders caused by cerebrovasculardiseases including, but not limited to, cerebral infarction, cerebralbleeding, cerebral arteriosclerosis, cerebral venous thrombosis, headinjuries, and the like and where symptoms include disturbances ofconsciousness, senile dementia, coma, lowering of attention, speechdisorders, and the like.

[0022] The terms “obsessive-compulsive disorder,” “substance abuse,”“pre-menstrual syndrome,” “anxiety,” “eating disorders” and “migraine”are used herein in a manner consistent with their accepted meanings inthe art. See, e.g., DSM-IV™. The terms “method of treating orpreventing,” “method of treating” and “method of preventing” when usedin connection with these disorders mean the amelioration, prevention orrelief from the symptoms and/or effects associated with these disorders.Without being limited by any theory, the treatment or prevention ofcertain of these disorders may be related to the activity of the activeingredient(s) as inhibitors of serotonin uptake.

[0023] As used herein, the term “a method of treating or preventingincontinence” means prevention of or relief from the symptoms ofincontinence including involuntary voiding of feces or urine, anddribbling or leakage or feces or urine which may be due to one or morecauses including but not limited to pathology altering sphinctercontrol, loss of cognitive function, overdistention of the bladder,hyper-reflexia and/or involuntary urethral relaxation, weakness of themuscles associated with the bladder or neurologic abnormalities.

4. DETAILED DESCRIPTION OF THE INVENTION

[0024] This invention relates to optically pure derivatives of(−)-venlafaxine such as, but not limited to, (−)-O-desmethylvenlafaxine,(−)-N-desmethylvenlafaxine, and (−)-N,O-didesmethylvenlafaxine. Thisinvention further relates to the synthesis of optically pure(−)-venlafaxine derivatives and to compositions (e.g., pharmaceuticalcompositions) comprising them. The invention also relates to novel usesof the compounds disclosed herein, which constitute improvements overthe use of racemic venlafaxine as well as over the optically pureisomers of venlafaxine.

[0025] One embodiment of the invention encompasses a method of treatingan affective disorder in a human which comprises administering to ahuman in need of such treatment a therapeutically effective amount of a(−)-venlafaxine derivative, preferably (−)-O-desmethylvenlafaxine, or apharmaceutically acceptable salt thereof, substantially free of its (+)stereoisomer. Venlafaxine derivatives, preferably(−)-O-desmethylvenlafaxine, can be used to treat an affective disorderwhile exhibiting a longer half life than venlafaxine and/or whileavoiding or reducing adverse effects that are associated with theadministration of venlafaxine.

[0026] Another embodiment of the invention encompasses a method oftreating weight gain or obesity in a human which comprises administeringto a human in need of weight loss or obesity therapy a therapeuticallyeffective amount of a (−)-venlafaxine derivative, preferably(−)-O-desmethylvenlafaxine, or a pharmaceutically acceptable saltthereof, substantially free of its (+) stereoisomer, said amount beingsufficient to reduce or prevent weight gain or obesity. Optically pure(−)-venlafaxine derivatives, preferably (−)-O-desmethylvenlafaxine, canbe used to treat weight gain or obesity disorder while exhibiting alonger half life than venlafaxine and/or while avoiding or reducingadverse effects that are associated with the administration ofvenlafaxine.

[0027] Another embodiment of the invention encompasses a method oftreating disorders ameliorated by neuronal monoamine reuptake inhibitionin a human which comprises administering to a human a therapeuticallyeffective amount of a (−)-venlafaxine derivative, preferably(−)-O-desmethylvenlafaxine, or a pharmaceutically acceptable saltthereof, substantially free of its (+) stereoisomer, said amount beingsufficient to treat such disorders. Disorders which are ameliorated byneuronal monoamine reuptake include, but are not limited to, Parkinson'sdisease, epilepsy, and depression. The optically pure derivative of(−)-venlafaxine may be used to treat such disorders while avoiding orreducing adverse effects associated with the administration ofvenlafaxine.

[0028] Optically pure, or substantially optically pure, (−)-venlafaxinederivatives, preferably (−)-O-desmethylvenlafaxine, and compositionscontaining them are also useful in treating cerebral function disorders.Such disorders include, but are not limited to, senile dementia,Alzheimer's type dementia, memory loss, amnesia/amnestic syndrome,disturbance of consciousness, coma, lowering of attention, speechdisorders, Parkinson's disease, Lennox syndrome, autism, hyperkineticsyndrome and schizophrenia. Cerebral function disorders may be inducedby factors including, but not limited to, cerebrovascular diseases suchas cerebral infarction, cerebral bleeding, cerebral arteriosclerosis,cerebral venous thrombosis, head injuries and the like and wheresymptoms include disturbances of consciousness, senile dementia, coma,lowering of attention, speech disorders and the like. Thus, theinvention encompasses a method of treating cerebral function disorder ina human which comprises administering to a human in need of such therapya therapeutically effective amount of (−)-venlafaxine derivative,preferably (−)-O-desmethylvenlafaxine, or a pharmaceutically acceptablesalt thereof, substantially free of its (+) stereoisomer. The use of anoptically pure (−)-venlafaxine derivative, preferably optically pure(−)-O-desmethylvenlafaxine, is intended to provide an improvement overthe use of the parent drug venlafaxine. The optically pure derivativesof the invention are more potent and yet provide an overall improvedtherapeutic index over venlafaxine.

[0029] Another embodiment of the invention encompasses a method oftreating pain, including chronic pain, in a human which comprisesadministering to a human in need of such therapy a therapeuticallyeffective amount of (−)-venlafaxine derivative, preferably(−)-O-desmethylvenlafaxine, or a pharmaceutically acceptable saltthereof, substantially free of its (+) stereoisomer, said amount beingsufficient to alleviate the human's pain.

[0030] Another embodiment of the invention encompasses a method oftreating an obsessive-compulsive disorder in a human, which comprisesadministering to a human in need of such therapy a therapeuticallyeffective amount of a (−)-venlafaxine derivative, preferably(−)-O-desmethylvenlafaxine, or a pharmaceutically acceptable saltthereof, substantially free of its (+) stereoisomer.

[0031] Another embodiment of the invention encompasses a method oftreating or preventing substance abuse in a human, which comprisesadministering to a human in need of such therapy a therapeuticallyeffective amount of a (−)-venlafaxine derivative, preferably(−)-O-desmethylvenlafaxine, or a pharmaceutically acceptable saltthereof, substantially free of its (+) stereoisomer.

[0032] Another embodiment of the invention encompasses a method oftreating or preventing pre-menstrual syndrome in a human, whichcomprises administering to a human in need of such therapy atherapeutically effective amount of a (−)-venlafaxine derivative,preferably (−)-O-desmethylvenlafaxine, or a pharmaceutically acceptablesalt thereof, substantially free of its (+) stereoisomer.

[0033] Another embodiment of the invention encompasses a method oftreating anxiety in a human, which comprises administering to a human inneed of such therapy a therapeutically effective amount of a(−)-venlafaxine derivative, preferably (−)-O-desmethylvenlafaxine, or apharmaceutically acceptable salt thereof, substantially free of its (+)stereoisomer.

[0034] Another embodiment of the invention encompasses a method oftreating an eating disorder in a human, which comprises administering toa human in need of such therapy a therapeutically effective amount of a(−)-venlafaxine derivative, preferably (−)-O-desmethylvenlafaxine, or apharmaceutically acceptable salt thereof, substantially free of its (+)stereoisomer.

[0035] Another embodiment of the invention encompasses a method oftreating or preventing a migraine, or migraine headaches, in a human,which comprises administering to a human in need of such therapy atherapeutically effective amount of a (−)-venlafaxine derivative,preferably (−)-O-desmethylvenlafaxine, or a pharmaceutically acceptablesalt thereof, substantially free of its (+) stereoisomer.

[0036] Another embodiment of the invention encompasses a method oftreating or preventing incontinence in a human which comprisesadministering to a human in need of such therapy a therapeuticallyeffective amount of a (−)-venlafaxine derivative, preferably(−)-O-desmethylvenlafaxine, or a pharmaceutically acceptable saltthereof, substantially free of its (+) stereoisomer. In particular, a(−)-venlafaxine derivative can be used to treat fecal incontinence,stress urinary incontinence (“SUI”), urinary exertional incontinence,urge incontinence, reflex incontinence, passive incontinence andoverflow incontinence. In a preferred embodiments the human is an elderperson of an age greater than 50 or a child of an age less than 13.Further, the invention encompasses the treatment of incontinence inpatients with either loss of cognitive function, sphincter control orboth. The invention is particularly well suited for the treatment orprevention of fecal incontinence and stress urinary incontinence.

[0037] Another embodiment of the invention encompasses a method ofpreparing (−)-N-desmethylvenlafaxine which comprises contacting acompound of Formula 5:

[0038] with a reductant for a time and at a temperature sufficient toform (±)-N-desmethylvenlafaxine, and isolating(−)-N-desmethylvenlafaxine therefrom. A preferred reductant is BH₃.Me₂S.

[0039] Another embodiment of the invention encompasses a method ofpreparing (−)-N,N-didesmethylvenlafaxine which comprises contacting acompound of Formula 2:

[0040] with a reductant for a time and at a temperature sufficient toform (+)-N,N-didesmethylvenlafaxine, and isolating(−)-N,N-didesmethylvenlafaxine therefrom. A preferred reductant isCoCl₂/NaBH₄.

[0041] Another embodiment of the invention encompasses a method ofpreparing (−)-O-desmethylvenlafaxine which comprises contacting(−)-venlafaxine with lithium diphenylphosphide for a time and at atemperature sufficient to form (−)-O-desmethylvenlafaxine.

[0042] Another embodiment of the invention encompasses a method ofpreparing (−)-O-desmethylvenlafaxine which comprises contacting(i)-venlafaxine with lithium diphenylphosphide for a time and at atemperature sufficient to form (+)-O-desmethylvenlafaxine, and isolating(−)-O-desmethylvenlafaxine therefrom.

[0043] Another embodiment of the invention encompasses substantiallypure (−)-O-desmethylvenlafaxine and pharmaceutically acceptable salts,solvates, and clathrates thereof.

[0044] Another embodiment of the invention encompasses substantiallypure (−)-N,O-didesmethylvenlafaxine and pharmaceutically acceptablesalts, solvates, and clathrates thereof.

[0045] Another embodiment of the invention encompasses(−)-N-desmethylvenlafaxine and pharmaceutically acceptable salts,solvates, and clathrates thereof.

[0046] A final embodiment of the invention encompasses(−)-N,N-didesmethylvenlafaxine and pharmaceutically acceptable salts,solvates, and clathrates thereof.

[0047] Compounds of the invention, which can be used and prepared asdescribed herein, are shown below in Scheme I(b):

[0048] The synthesis of some venlafaxine derivatives has been describedby Yardley, J. P. et al. J. Med. Chem. 33:2899-2905 (1990), thedisclosure of which is hereby incorporated by reference. This method,which may be adapted for the synthesis of the compounds of thisinvention, is shown in Scheme II:

[0049] wherein R is methoxy or hydroxy, R₁ is hydrogen or methyl, andthe reaction conditions are as follows: (a) LDA in cycloalkanone at −78°C.; (b) Rh/Al₂O₃; and (c) HCHO, HCOOH, H₂O, reflux. The (−) isomer ofthe racemic final product yielded by step (c) may be isolated by anymethod known to those skilled in the art, including high performanceliquid chromatography (HPLC) and the formation and crystallization ofchiral salts. See, e.g., Jacques, J., et al., Enantiomers, Racemates andResolutions, (Wiley-Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed. Univ. of NotreDame Press, Notre Dame, Ind., 1972). As used herein, the term “isolate”encompasses the isolation of a compound from a reaction mixture, thepurification of the compound, and the optical resolution of thecompound.

[0050] In a preferred method of the invention,(−)-N,N-didesmethylvenlafaxine is prepared from(i)-N,N-didesmethylvenlafaxine, which itself is preferably preparedaccording to the method shown in Scheme III:

[0051] According to this method, cyclohexanone is reacted with compound1 to provide compound 2. This reaction is preferably done in thepresence of a catalyst such as, but not limited to, lithiumdiisopropylamide (LDA), and in an aprotic solvent such as, but notlimited to, THF. The cyano group of compound 2 is subsequently contactedwith a reductant to provide compound 3, (±)-N,N-didesmethylvenlafaxine.A preferred reductant is CoCl₂/NaBH₄ in methanol, although otherreductants known to those skilled in the art can also be used. Salts of(+)-N,N-didesmethylvenlafaxine, such as the HCl salt (compound 4), canthen be formed using reaction conditions well known in the art.(−)-N,N-didesmethylvenlafaxine can be isolated from(±)-N,N-didesmethylvenlafaxine using methods known in the art (e.g., bythe formation of a chiral salt or using chiral chromatography).

[0052] Referring again to Scheme III, (−)-N,N-didesmethylvenlafaxine canalternatively be prepared from the appropriate enantiomer of compound 2.Optically pure enantiomers of compound 2 can be isolated using methodsknown in the art (by the formation of a chiral salt or using chiralchromatography).

[0053] In another preferred method of the invention,(−)-N-desmethylvenlafaxine is prepared from (±)-N-desmethylvenlafaxine,which itself is prepared from (±)-N,N-didesmethylvenlafaxine accordingto the method shown in Scheme IV:

[0054] According to this method, (±)-N,N-didesmethylvenlafaxine(compound 3) is converted to compound 5 using, for example, HCO₂H in asolvent such as, but not limited to, toluene. The aldehyde of compound 5is subsequently reduced to provide compound 6,(±)-N-desmethylvenlafaxine. A preferred reductant is BH₃.Me₂S in anaprotic solvent such as, but not limited to, THF. Salts of(±)-N-desmethylvenlafaxine, such as the HCl salt (compound 7), can thenbe formed using reaction conditions well known in the art.(−)-N-desmethylvenlafaxine can be isolated from(±)-N-desmethylvenlafaxine using methods known in the art (e.g., by theformation of a chiral salt or using chiral chromatography).

[0055] Referring again to Scheme IV, (−)-N-desmethylvenlafaxine canalternatively be prepared from the appropriate enantiomers of compounds3 or 5. Optically pure enantiomers of compounds 3 and 5 can be isolatedusing methods known in the art (e.g., by the formation of a chiral saltor using chiral chromatography).

[0056] It is also possible to prepare the compounds of the inventionfrom racemic venlafaxine, which can be prepared according to methodsdisclosed, for example, by U.S. Pat. No. 4,761,501 and Pento, J. T.Drugs of the Future 13(9):839-840 (1988), both of which are incorporatedherein by reference. Optically pure (−)-venlafaxine can be isolated fromthe racemic mixture by conventional means such as those described above,and then selectively demethylated according to methods known to thoseskilled in the art. See, e.g., March, J. Advanced Organic Chemistry p.361 (3^(rd) ed. 1985).

[0057] In a preferred method of the invention, optically pure(−)-venlafaxine is isolated from (±)-venlafaxine according to the methodshown in Scheme V:

[0058] According to this method, (−)-venlafaxine (compound 9) isisolated from (±)-venlafaxine (compound 8) by forming a chiral saltusing, for example, di-p-toluoyl-D-tartaric acid. Salts of(−)-venlafaxine, such as the HCl salt (compound 10), can then be formedusing reaction conditions well known in the art.

[0059] Compounds of the invention are readily prepared from(−)-venlafaxine. For example, in a preferred method of the invention,(−)-O-desmethylvenlafaxine is prepared from (−)-venlafaxine as shown inScheme VI:

[0060] According to this method, the methoxy group of (−)-venlafaxine(compound 9) is converted to an alcohol to provide(−)-O-desmethylvenlafaxine (compound 11) using, for example, lithiumdiphenylphosphide.

[0061] Alternative methods of preparing (±)-venlafaxine HCl and(±)-O-desmethylvenlafaxine, from which optically pure (−)-venlafaxinederivatives can be prepared using methods such as those describedherein, are shown in Scheme VII:

[0062] According to Scheme VII, (±)-venlafaxine (compound 8) is preparedby reacting (±)-N,N-didesmethylvenlafaxine (compound 3) with, forexample, HCHO/HCO₂H. Compound 8 can then be converted to(+)-O-desmethylvenlafaxine (compound 13) using, for example, lithiumdiphenylphosphide. Alternatively, salts of (±)-venlafaxine, such as theHCl salt (compound 12), can be formed using reaction conditions wellknown in the art. Optically pure enantiomers of compounds 12 and 13 canbe isolated using methods known to those skilled in the art (e.g., bythe formation of a chiral salt or using chiral chromatography).Optically pure enantiomers of compounds 12 and 13 can also be preparedaccording to Scheme VII by beginning with the corresponding opticallypure enantiomers of compound 8.

[0063] Utilizing the optically pure or substantially optically purederivatives of (−)-venlafaxine in the treatment and/or mitigation of theconditions described herein results in clearer dose-related definitionsof efficacy, diminished adverse effects, and accordingly an improvedtherapeutic index as compared to venlafaxine itself.

[0064] The magnitude of a prophylactic or therapeutic dose of a(−)-venlafaxine derivative (herein also referred to as an “activeingredient”), preferably (−)-O-desmethylvenlafaxine, in the acute orchronic management of a disease will vary with the severity of thecondition to be treated and the route of administration. The dose, andperhaps the dose frequency, will also vary according to age, bodyweight, response, and the past medical history of the individualpatient. In general, the recommended daily dose range for the conditionsdescribed herein lie within the range of from about 10 mg to about 1000mg per day, given as a single once-a-day dose in the morning butpreferably as divided doses throughout the day taken with food.Preferably, a daily dose range should be from about 50 mg to about 500mg per day, more preferably, between about 75 mg and about 350 mg perday. In managing the patient, the therapy should be initiated at a lowerdose, perhaps about 50 mg to about 75 mg, and increased if necessary upto about 250 mg to about 325 mg per day as either a single dose ordivided doses, depending on the patient's global response. If a dosageis increased, it is preferably done in intervals of about 75 mgseparated by at least 4 days.

[0065] Because elimination of (−)-venlafaxine derivatives from thebloodstream is dependant on renal and liver function, it is recommendedthat the total daily dose be reduced by at least 50% in patients withmoderate hepatic impairment, and that it be reduced by 25% in patientswith mild to moderate renal impairment. For patients undergoinghemodialysis, it is recommended that the total daily dose be reduced by5% and that the dose be withheld until the dialysis treatment iscompleted. Because some adverse reactions have been reported forpatients who took venlafaxine concurrently with, or shortly after, amonamine oxidase inhibitor, it is recommended that the (−)-venlafaxinederivatives of this invention not be administered to patients currentlytaking such inhibitors. In general, the concurrent administration of thecompounds of this invention with other drugs, particularly otherserotonin uptake inhibitors, should be done with care. See, e.g., vonMoltke, L. L. et al. Biol. Psychiatry 41:377-380 (1997); and Sinclair,J. et al. Rev. Contemp. Pharmacother. 9:333-344 (1998).

[0066] The various terms “said amount being sufficient to alleviate theaffective disorder,” “said amount being sufficient to alleviatedepression,” “said amount being sufficient to alleviate attentiondeficit disorder,” “said amount being sufficient to alleviate anobsessive-compulsive disorder”, “said amount being sufficient to preventor alleviate substance abuse”, “said amount being sufficient to preventor alleviate pre-menstrual syndrome”, “said amount being sufficient toprevent or alleviate anxiety”, “said amount being sufficient to preventor alleviate an eating disorder”, “said amount being sufficient toprevent or alleviate or prevent migraine”, “said amount being sufficientto alleviate Parkinson's disease,” “said amount being sufficient toalleviate epilepsy,” “said amount being sufficient to alleviate obesityor weight gain,” “an amount sufficient to achieve weight loss,” “saidamount being sufficient to bring about weight reduction in a human,”“said amount being sufficient to alleviate pain,” “said amount beingsufficient to alleviate dementia,” “said amount sufficient to alleviatesaid disorders ameliorated by inhibition of neuronal monoaminereuptake,” “said amount is sufficient to alleviate cerebral functiondisorders” wherein said disorders are selected from the group consistingof senile dementia, Alzheimer's type dementia, memory loss,amnesia/amnestic syndrome, disturbance of consciousness, coma, loweringof attention, speech disorders, Parkinson's disease, Lennox syndrome,autism, hyperkinetic syndrome, schizophrenia, and cerebrovasculardiseases, such as cerebral infarction, cerebral bleeding, cerebralarteriosclerosis, cerebral venous thrombosis, head injuries, and thelike, “said amount being sufficient to treat or prevent incontinence”wherein said incontinence includes but is not limited to fecal, stress,urinary, urinary exertional, urge, reflex, passive and overflowincontinence, are encompassed by the above described dosage amounts anddose frequency schedule. Similarly, amounts sufficient to alleviate eachof the above disorders but insufficient to cause adverse effectsassociated with venlafaxine are also encompassed by the above describeddosage amounts and dose frequency schedule.

[0067] Any suitable route of administration can be employed forproviding the patient with a therapeutically or prophylacticallyeffective dose of an active ingredient. For example, oral, mucosal(e.g., nasal, sublingual, buccal, rectal, vaginal), parenteral (e.g.,intravenous, intramuscular), transdermal, and subcutaneous routes can beemployed. Preferred routes of administration include oral, transdermal,and mucosal. Suitable dosage forms for such routes include, but are notlimited to, transdermal patches, ophthalmic solutions, sprays, andaerosols. Transdermal compositions can also take the form of creams,lotions, and/or emulsions, which can be included in an appropriateadhesive for application to the skin or can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose. A preferred transdermal dosage form is a “reservoir type”or “matrix type” patch, which is applied to the skin and worn for aspecific period of time to permit the penetration of a desired amount ofactive ingredient. The patch can be replaced with a fresh patch whennecessary to provide constant administration of the active ingredient tothe patient.

[0068] Other dosage forms of the invention include, but are not limitedto, tablets, caplets, troches, lozenges, dispersions, suspensions,suppositories, ointments, cataplasms (poultices), pastes, powders,dressings, creams, plasters, solutions, capsules, soft elastic gelatincapsules, and patches.

[0069] In practical use, an active ingredient can be combined in anintimate admixture with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier can takea wide variety of forms depending on the form of preparation desired foradministration. In preparing the compositions for an oral dosage form,any of the usual pharmaceutical media can be employed as carriers, suchas, for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents, and the like in the case of oral liquidpreparations (such as suspensions, solutions, and elixirs) or aerosols;or carriers such as starches, sugars, micro-crystalline cellulose,diluents, granulating agents, lubricants, binders, and disintegratingagents can be used in the case of oral solid preparations, preferablywithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oral preparationsbeing preferred over the liquid preparations.

[0070] Because of their ease of administration, tablets and capsulesrepresent the most advantageous oral dosage unit forms, in which casesolid pharmaceutical carriers are employed. If desired, tablets can becoated by standard aqueous or nonaqueous techniques.

[0071] In addition to the common dosage forms set out above, an activeingredient can also be administered by controlled release means ordelivery devices that are well known to those of ordinary skill in theart, such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767,5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, thedisclosures of which are incorporated herein by reference. These dosageforms can be used to provide slow or controlled-release of one or moreactive ingredients using, for example, hydropropylmethyl cellulose,other polymer matrices, gels, permeable membranes, osmotic systems,multilayer coatings, microparticles, liposomes, or microspheres or acombination thereof to provide the desired release profile in varyingproportions. Suitable controlled-release formulations known to those ofordinary skill in the art, including those described herein, can bereadily selected for use with the pharmaceutical compositions of theinvention. The invention thus encompasses single unit dosage formssuitable for oral administration such as, but not limited to, tablets,capsules, gelcaps, and caplets that are adapted for controlled-release.

[0072] All controlled-release pharmaceutical products have a common goalof improving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include: 1) extended activity of the drug; 2) reduceddosage frequency; and 3) increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and thus can affect the occurrence of side effects.

[0073] Most controlled-release formulations are designed to initiallyrelease an amount of drug that promptly produces the desired therapeuticeffect, and to gradually and continually release of other amounts ofdrug to maintain this level of therapeutic effect over an extendedperiod of time. In order to maintain this constant level of drug in thebody, the drug must be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousinducers, including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

[0074] Pharmaceutical compositions of the invention suitable for oraladministration can be presented as discrete dosage forms, such ascapsules, cachets, or tablets, or aerosol sprays each containing apredetermined amount of an active ingredient as a powder or in granules,a solution, or a suspension in an aqueous or non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosageforms can be prepared by any of the methods of pharmacy, but all methodsinclude the step of bringing the active ingredient into association withthe carrier, which constitutes one or more necessary ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product intothe desired presentation.

[0075] For example, a tablet can be prepared by compression or molding,optionally with one or more accessory ingredients. Compressed tabletscan be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient such as, but not limited to, a binder, alubricant, an inert diluent, and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.

[0076] This invention further encompasses lactose-free pharmaceuticalcompositions and dosage forms. Lactose is used as an excipient invenlafaxine formulations. See, e.g., Physician's Desk Reference® 3294(53^(rd) ed., 1999). Unlike the parent drug, however, N-demethylatedderivatives of (−)-venlafaxine (e.g., (−)-N-desmethylvenlafaxine and(−)-N,N-didesmethylvenlafaxine), are secondary or primary amines and maythus decompose over time when exposed to lactose. Consequently,compositions of the invention that comprise N-demethylated derivativesof (−)-venlafaxine preferably contain little, if any, lactose or othermono- or di-saccharides. As used herein, the term “lactose-free” meansthat the amount of lactose present, if any, is insufficient tosubstantially increase the degradation rate of an active ingredient.

[0077] Lactose-free compositions of the invention can compriseexcipients which are well known in the art and are listed in the USP(XXI)/NF (XVI), which is incorporated herein by reference. In general,lactose-free compositions comprise an active ingredient, abinder/filler, and a lubricant in pharmaceutically compatible andpharmaceutically acceptable amounts. Preferred lactose-free dosage formscomprise an active ingredient, microcrystalline cellulose,pre-gelatinized starch, and magnesium stearate.

[0078] This invention further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example, theaddition of water (e.g., 5%) is widely accepted in the pharmaceuticalarts as a means of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,water and heat accelerate decomposition. Thus the effect of water on aformulation can be of great significance since moisture and/or humidityare commonly encountered during manufacture, handling, packaging,storage, shipment, and use of formulations.

[0079] Anhydrous pharmaceutical compositions and dosage forms of theinvention can be prepared using anhydrous or low moisture containingingredients and low moisture or low humidity conditions. Pharmaceuticalcompositions and dosage forms of the invention which contain lactose arepreferably anhydrous if substantial contact with moisture and/orhumidity during manufacturing, packaging, and/or storage is expected.

[0080] An anhydrous pharmaceutical composition should be prepared andstored such that its anhydrous nature is maintained. Accordingly,anhydrous compositions are preferably packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastic or the like, unit dosecontainers, blister packs, and strip packs.

[0081] In this regard, the invention encompasses a method of preparing asolid pharmaceutical formulation comprising an active ingredient whichmethod comprises admixing under anhydrous or low moisture/humidityconditions the active ingredient and an excipient (e.g., lactose),wherein the ingredients are substantially free of water. The method canfurther comprise packaging the anhydrous or non-hygroscopic solidformulation under low moisture conditions. By using such conditions, therisk of contact with water is reduced and the degradation of the activeingredient can be prevented or substantially reduced.

[0082] Binders suitable for use in pharmaceutical compositions anddosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[0083] Suitable forms of microcrystalline cellulose include, forexample, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, and AVICEL-PH-105 (available from FMC Corporation, AmericanViscose Division, Avicel Sales, Marcus Hook, Pa., U.S.A.). An exemplarysuitable binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

[0084] Examples of suitable fillers for use in the pharmaceuticalcompositions and dosage forms disclosed herein include, but are notlimited to, talc, calcium carbonate (e.g., granules or powder),microcrystalline cellulose, powdered cellulose, dextrates, kaolin,mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, andmixtures thereof. The binder/filler in pharmaceutical compositions ofthe present invention is typically present in about 50 to about 99weight percent of the pharmaceutical composition.

[0085] Disintegrants are used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant will produce tablets which maydisintegrate in the bottle. Too little may be insufficient fordisintegration to occur and may thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s)should be used to form the dosage forms of the compounds disclosedherein. The amount of disintegrant used varies based upon the type offormulation and mode of administration, and is readily discernible tothose of ordinary skill in the art. Typically, about 0.5 to about 15weight percent of disintegrant, preferably about 1 to about 5 weightpercent of disintegrant, can be used in the pharmaceutical composition.

[0086] Disintegrants that can be used to form pharmaceuticalcompositions and dosage forms of the invention include, but are notlimited to, agar-agar, alginic acid, calcium carbonate, microcrystallinecellulose, croscarmellose sodium, crospovidone, polacrilin potassium,sodium starch glycolate, potato or tapioca starch, other starches,pre-gelatinized starch, other starches, clays, other algins, othercelluloses, gums or mixtures thereof.

[0087] Lubricants which can be used to form pharmaceutical compositionsand dosage forms of the invention include, but are not limited to,calcium stearate, magnesium stearate, mineral oil, light mineral oil,glycerin, sorbitol, mannitol, polyethylene glycol, other glycols,stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil(e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil,corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate,agar, or mixtures thereof. Additional lubricants include, for example, asyloid silica gel (AEROSIL 200, manufactured by W. R. Grace Co. ofBaltimore, Md.), a coagulated aerosol of synthetic silica (marketed byDegussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxideproduct sold by Cabot Co. of Boston, Mass.), or mixtures thereof. Alubricant can optionally be added, typically in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

[0088] Desirably, each tablet contains from about 25 mg to about 150 mgof the active ingredient and each cachet or capsule contains from about25 mg to about 150 mg of the active ingredient. Most preferably, thetablet, cachet, or capsule contains either one of three dosages, e.g.,about 25 mg, about 50 mg, or about 75 mg of active ingredient (as scoredtablets, the preferable dose form).

[0089] The invention is further defined by reference to the followingexamples describing in detail the preparation of the compositions of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the purpose and interest of this invention.

5. EXAMPLES

[0090] As discussed above, at least two different synthetic approachesmay be utilized to obtain the compounds of this invention. A first isbased upon the isolation of (−)-venlafaxine, followed by selectivedemethylation. In a second approach, racemic mixtures of venlafaxinederivatives are separated into their optically pure components. 5.1.EXAMPLE 1: Synthesis and Resolution of (−)-Venlafaxine1-[cyano-(4-methoxyphenyl)methyl]cyclohexanol

[0091] A solution of 4-methoxybenzylnitrile (53.5 g, 0.36 mol) in 400 mLTHF was cooled to −78° C. followed by slow addition of a 2.0 M THFsolution of lithium diisopropylamide (200 mL, 0.40 mol) maintaining thereaction temperature below −65 ° C. The reaction was stirred at −78° C.for 30 minutes. Cyclohexanone (39.5 g, 0.40 mol) was added at a ratesuch that the reaction temperature did not rise above −65° C. After theaddition reaction was stirred at −78° C. for 2 hours, then was pouredinto 1 L saturated aqueous NH₄Cl containing ice. The mixture was stirredfor 15 minutes and was extracted with ethyl acetate (4×200 mL). Combinedethyl acetate layer was washed with water (3×100 mL), brine (1×100 mL)and dried (Na₂SO₄). Ethyl acetate was evaporated in vacuo to givecolorless solid that was trichurated with hexane. The precipitate wasfiltered, washed with hexane, dried in vacuo to give colorless solid(72.0 g, 80.7% yield). ¹H (CDCl₃): 7.30 and 6.90 (q, 4H), 3.80 (s, 3H),3.75 (s, 1H), 1.55 (m, 10H); ¹³C (CDCl₃): 159.8, 130.8, 123.8, 120.0,114.1, 72.9, 55.5, 49.5, 34.9, 25.3, 21.6.

[0092] 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol

[0093] A 3-L, three-neck flask equipped with a mechanical stirrer and athermocouple was charged with1-[cyano(4-methoxyphenyl)methyl]cyclohexanol (40.0 g, 0.16 mol) and 1 Lmethanol. To the resulting stirred solution was added cobalt chloride(42.4 g, 0.32 mol) and the reaction was stirred until a clear dark bluesolution was obtained. Sodium borohydride (62.0 g, 1.63 mol) was addedin small lots maintaining the reaction temperature below 35° C. A darkblack precipitate was formed along with vigorous evolution of gas assoon as sodium borohydride was added. After completion of addition theslurry was stirred at room temperature for 2 hours. TLC examinationindicated complete disappearance of the starting material. The reactionwas cooled in ice/water and 1 L 3N HCl was added slowly. Reactiontemperature was maintained below 25° C. Reaction was stirred for 30minutes after completion of the addition. Small amount of blackprecipitate was still observed. Methanol was removed in vacuo followedby extraction of the aqueous layer with ethyl acetate (3×300 mL). Theaqueous layer was cooled in ice/water and was basified (pH paper) byslow addition of concentrated NH₄OH (˜600 mL). Reaction temperature wasmaintained below 25° C. Reaction was extracted with ethyl acetate (4×200mL). Combined ethyl acetate layer was washed with water (3×100 mL),brine (1×100 mL), and dried (Na₂SO₄). Ethyl acetate was evaporated invacuo to give yellow gum (34.0 g, 83.6% yield). ¹H (CDCl₃): 7.20 and6.85 (q, 4H), 3.80 (s, 3H), 3.20 (m, 2H), 2.70 (t, 3H), 2.35 (br s, 3H),1.40 (m, 10H); ³C (CDCl₃): 158.4, 132.6, 130.6, 113.7, 73.7, 56.7, 55.3,42.4, 37.3, 34.5, 26.0, 21.9.

[0094] (±)-Venlafaxine

[0095] 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol (33.0 g, 0.13mol) was dissolved in 88% formic acid (66.0 g, 55 mL, 1.43 mol) andwater (330 mL) followed by addition of 37% aqueous formaldehyde (44.4 g,41 mL, 1.48 mol). The resulting solution was refluxed for 20 hours,cooled to room temperature and was concentrated to 150 mL, adjusted topH 2.0 with 3N HCl, and extracted with ethyl acetate (˜6×50 mL) untilpink impurity was removed. The aqueous layer was cooled in ice/water andwas basified by slow addition of 50% NaOH. The aqueous layer wasextracted with ethyl acetate (3×75 mL). Combined ethyl acetate layer waswashed with water (3×25 mL), brine (1×25 mL) and dried (Na₂SO₄). Ethylacetate was evaporated in vacuo to give yellow gum that turned slowly into pale yellow solid (34.0 g, 92.6% yield). ¹H (CDCl₃): 7.05 and 6.80(q, 4H), 3.80 (s, 3H), 3.30 (t, 1H), 2.95 (dd, 1H), 2.35 (s, 6 H), 2.30(dd, 1H), 1.30 (m, 10H); ¹³C (CDCl₃): 158.4, 132.9, 130.3, 113.5, 74.4,61.4, 55.3, 51.8, 45.6, 38.2,31.3,26.2, 21.8, 21.5. MS (277, M+).

[0096] (±)-Venlafaxine-HCl Salt

[0097] A solution of (i)-venlafaxine (1.0 g, 3.6 mmol) in 100 mL MTBEwas cooled to 0° C. and 2 mL of 15% HCl in MTBE was added to it. Acolorless precipitate was formed. The reaction was stirred at 0° C. for10 minutes. Solid was filtered, washed with MTBE, dried in vacuo to givethe product as colorless solid (0.700 g, 61.9% yield). ¹H (CDCl₃): 11.40(s, 1H), 7.15 and 6.85 (q, 4H), 4.05 (d, 1H), 3.80 (s, 3H), 3.35 (t,1H), 3.20 (m, 2H), 2.80 (s, 3H), 2.60 (s, 3H), 1.30 (m, 10H); ¹³C(CDCl₃): 159.0, 131.4, 130.3, 114.2, 73.7, 60.4, 55.4, 52.7, 45.3, 42.8,36.7, 31.5, 25.5, 21.7, 21.3. MS (277, M+for free base). % purity(HPLC): 99.62.

[0098] Tartrate Salts of Venlafaxine

[0099] To a stirred solution of (±)-venlafaxine (20.0 g, 0.072 mol) in150 mL ethyl acetate was added a solution of di-p-toluoyl-D-tartaricacid (16.0 g, 0.041 mol) in 120 mL ethyl acetate. Mild exotherm wasobserved. Colorless solid started precipitating out within 15 minutes.The suspension was stirred at room temperature for 4 hours. The solidwas filtered, washed with ethyl acetate, dried in vacuo to give(R)-venlafaxine-di-p-toluoyl-D-tartrate salt as colorless solid (18.0 g,37.6% yield).

[0100] Combined mother liquors from above reaction were washed withice-cold 1N NaOH (4×100 mL), water (3×200 mL), brine (1×100 mL), dried(Na₂SO₄). Ethyl acetate was evaporated in vacuo to give colorless solid(10.8 g, 0.039 mol). This solid was dissolved in 75 mL of ethyl acetateand a solution of di-p-toluoyl-L-tartaric acid (11.3 g, 0.029 mol) in 75mL ethyl acetate was added to it. Colorless solid started precipitatingout within 30 minutes. Additional amount of ethyl acetate (50 mL) wasadded to the slurry and it was stirred overnight at RT. The solid wasfiltered, washed with ethyl acetate, dried in vacuo to give(S)-venlafaxine-di-p-toluoyl-L-tartrate salt as colorless solid (13.0 g,50.0% yield).

[0101] Crystallization of the Tartrate Salt

[0102] (R)-Venlafaxine-di-p-toluoyl-D-tartrate salt (18.0 g, 0.027 mol)was suspended in 250 mL ethyl acetate/ methanol (6:1) and the suspensionwas warmed to 60° C. until a clear solution was obtained. The solutionwas allowed to cool to room temperature and stirred overnight. Solid wasfiltered, washed with ethyl acetate/ methanol (6:1), dried. Thisprocedure was repeated two more times. After three crystallizations theproduct was obtained as colorless solid (5.76 g, 32.0% yield), e.e.(HPLC): >99.95.

[0103] (−)-Venlafaxine

[0104] 50 mL cold 2N NaOH was added to(R)-(−)-venlafaxine-di-p-toluoyl-D-tartrate salt (5.3 g, 8.0 mmol) andthe aqueous layer was extracted with ethyl acetate (3×100 mL). Combinedethyl acetate layer was washed with cold 2N NaOH (1×25 mL) and wateruntil aqueous wash was neutral. Ethyl acetate layer was dried (Na₂SO₄),ethyl acetate evaporated to give (−)-venlafaxine as colorless solid (2.2g, quantitative yield), e.e. (HPLC): >99.95. ¹H, ¹³C and MS data as in(±)-venlafaxine.

[0105] (−)-Venlafaxine-HCl Salt

[0106] (−)-venlafaxine HCl salt was prepared from (−)-venlafaxine byfollowing the procedure described for making (±)-venlafaxine HCl salt.

[0107] (−)-Venlafaxine-HCl Salt: colorless solid, [α]_(D)=−2.4 (c=0.25,EtOH), % purity (HPLC): 99.94, e.e. (HPLC): >99.99. ¹H, ¹³C and MS dataas in (±)-venlafaxine HCl.

5.2. EXAMPLE 2: Synthesis and Resolution of (−)-O-desmethylvenlafaxine

[0108] (±)-O-desmethylvenlafaxine

[0109] A solution of diphenylphosphine (3.0 g, 16.1 mmol) in 20 mL THFwas cooled to −10° C. followed by slow addition of a 1.6 M THF solutionof n-BuLi (12.7 mL, 20.2 mmol) at a rate such that reaction temperaturedid not rise above 0C. The reaction was stirred at 0° C. for 30 minutes.A solution of (±)-venlafaxine (1.0 g, 3.6 mmol) in 10 mL THF was addedslowly at 0° C. The reaction was stirred at 0° C. for 15 minutes andallowed to warm to room temperature and stirred for 1 hour. It was thenrefluxed overnight. The reaction was cooled to room temperature and waspoured slowly into 30 mL cold 3N HCl maintaining the temperature below15° C. After stirring for 10 minutes, the aqueous layer was extractedwith ethyl acetate (3×30 mL). The aqueous layer was adjusted to pH6.8-6.9 by slow addition of solid NaHCO₃. It was then saturated byadding NaCl and was extracted with ethyl acetate (6×30 mL). Combinedethyl acetate layer was dried (Na₂SO₄), ethyl acetate was evaporated invacuo to give colorless solid. The solid was trichurated with cold ethylacetate, filtered, washed with cold ethyl acetate to give colorlesssolid (0.700 g, 73.8% yield). ¹H (DMSO, d₆): 9.30 (br s, 1H); 7.10 and6.80 (q, 4H), 5.60 (br s, 1H), 3.15 (dd, 1H), 2.88 (t, 1H), 2.50 (dd,1H), 2.30 (s, 6H), 1.35 (m, 10H); ¹³C (DMSO, d₆): 155.5, 131.7, 130.1,114.4, 72.6, 60.4, 51.6, 45.3, 37.2, 32.4, 25.7, 21.2. MS: (264, M+1). %purity (HPLC): 99.9.

[0110] (−)-O-desmethylvenlafaxine

[0111] (−)-O-desmethylvenlafaxine was prepared from (−)-venlafaxine byfollowing the procedure described above.

[0112] (−)-O-desmethylvenlafaxine: colorless solid, [α]_(D)=−35.2(c=0.25, EtOH), % purity (HPLC): >99.99, e.e. (HPLC): >99.99.¹H, ¹³C andMS data as in (±)-O-demethylvenlafaxine.

5.3. EXAMPLE 3: Synthesis of (−)-N-desmethylvenlafaxine

[0113] (±)-N-desmethylvenlafaxine

[0114] To a solution of 1-[amino (4-methoxyphenyl)ethyl]cyclohexanol(1.0 g, 4.0 mmol) in 8 mL of toluene, 96% formic acid (0.37 g, 8.0 mmol)was added and the reaction was refluxed for 4 hours. It was cooled toroom temperature and poured into 40 mL saturated aqueous NaHCO₃. Toluenelayer was separated and aqueous layer was extracted with toluene (3×15mL). Combined toluene layer was washed with water (3×15 mL), brine (1×15mL) and dried (Na₂SO₄). Toluene was evaporated in vacuo to give crudeN-formyl compound as yellow gum (0.930 g, 83.8% yield). ¹H (CDCl₃): 7.95(s, 1H), 7.15 and 6.85 (q, 4H), 5.80 (s, 1H), 4.10 (m, 1H), 3.80 (s,3H), 3.50 (s, 1H), 2.80 (dd, 1H), 1.50 (m, 10H); ¹³C (CDCl₃):161.4,158.8, 131.0, 130.7, 113.9, 73.0, 55.3, 54.2, 38.1, 36.1, 35.6,25.6, 21.9, 21.8. (Impurity: 164.5, 129.0, 128.0, 125.0, 56.5, 42.0,36.5, 35.5). MS (277, M+).

[0115] To a solution of crude N-formyl compound (0.585 g, 2.1 mmol) in 6mL THF was added BH₃.Me₂S (0.480 g, 0.63 mL of 10 M solution, 6.3 mmol)slowly at 0° C. The reaction was allowed to warm to room temperature andthen was refluxed for 5 hours. It was cooled to 0° C. and 5 mL ofmethanol was added very carefully controlling the temperature below 10°C. The reaction was stirred for 10 minutes and volatiles were evaporatedoff. Residue was partitioned between 3N HCl (20 mL) and ethyl acetate(20 mL). Organic layer was separated and aqueous layer was extractedwith ethyl acetate (3×5 mL). Aqueous layer was cooled to 0° C. and wasbasified by slow addition of conc. NH₄OH. Aqueous layer was saturatedwith NaCl and was extracted with ethyl acetate (3×20 mL). Combined ethylacetate layer was dried (Na₂SO₄), ethyl acetate was evaporated in vacuoto give colorless oil (0.493 g, 88.8% yield). ¹H (CDCl₃): 7.15 and 6.85(q, 4H), 3.80 (s, 3H), 3.25 (dd, 1H), 2.95 (dd, 1H), 2.82 (dd, 1H), 2.45(s, 3H), 1.40 (m, 10H); ¹³C (CDCl₃): 158.4, 133.0, 130.5, 113.7, 73.9,55.4, 53.8, 53.0, 37.8, 36.5, 33.7, 26.0, 21.9.

[0116] (±)-N-desmethylvenlafaxine HCl Salt

[0117] To a solution of crude (±)-N-demethylvenlafaxine (0.450 g, 1.7mmol) in 25 mL MTBE was added 1 mL of 15% HCl in MTBE at 0° C. Theresulting slurry was stirred at 0° C. for 15 minutes, filtered, solidwas washed with MTBE, dried in vacuo to give the product as colorlesssolid (0.380 g, 74.2% yield). 1H (CDCl3): 9.10 (br d, 1H), 7.15 and 6.85(q, 4H), 3.80 (m & s,4H ),3.35 (dd, 1H), 3.15 (m, 1H), 2.70 (t, 3H),1.30 (m, 10H); ¹³C (CDCl₃): 159.0, 130.71, 130.4, 114.0, 74.7, 55.4,52.8, 50.9, 37.0, 34.1,30.9, 25.5, 21.4. % Purity (HPLC): 98.81.

[0118] (−)-N-desmethylvenlafaxine

[0119] Resolution of optically pure (−)-N-desmethylvenlafaxine may beperformed using the methods described herein. If chiral salts are to beused, the amine is preferably protected before formation of the salt.Suitable means of protecting the amines are known to those skilled inthe art and include, for example, reaction with phenacylsulfonylchloride to yield the corresponding sulfonamide, which can be removedafter isolation of the optically pure enantiomer with zinc and aceticacid. See, e.g., March, J. Advanced Organic Chemistry p. 445 (₃rd ed.1985).

5.4. EXAMPLE 4: Synthesis of (+)-N,N-didesmethylvenlafaxine HCl Salt

[0120] To a solution of 1-[amino (4-methoxyphenyl)ethyl]cyclohexanol(0.750 g, 3.0 mmol) in 75 mL MTBE was added 2 mL of 15% HCl in MTBE. Thereaction was stirred at 0° C. for 15 minutes. It was then evaporated todryness and the residue was trichurated with MTBE/hexane (6:4). Solidwas filtered, washed with MTBE/hexane (6:4). The solid was suspended incold MTBE, filtered, washed with cold MTBE, dried in vacuo to give theproduct as colorless solid (0.450 g, 52.3% yield). ¹H (DMSO, d₆)): 7.80(br s, 2H), 7.20 and 6.90 (q, 4H), 4.50 (br s, 1H), 3.80 (s, 3H), 3.40(m, 1H), 3.10 (m, 1H), 2.90 (m, 1H), 1.35 (m, 10H); ¹³C (DMSO, d₆):158.3, 130.7, 130.0, 113.5, 71.7, 54.9, 52.6, 36.3, 33.6, 26.8, 25.3,21.4, 21.1.% Purity (UPLC): 99.3.

5.5. EXAMPLE 5: Synthesis of (+)-O-desmethyl-N,N-didesmethylvenlafaxine

[0121] To a solution of diphenylphosphine (22.2 g, 0.12 mol) in 175 mlTHF was added a 1.6 M THF solution of n-BuLi (94 mL, 0.15 mol) slowlymaintaining the reaction temperature between −10° C. to 0C. After theaddition reaction was stirred at 0° C. for 30 minutes. A solution of(±)-N,N-didemethylvenlafaxine 13 (5.4 g, 0.021 mol) in 55 mL THF wasadded slowly at 0° C. The reaction mixture was stirred at 0° C. for 30minutes and allowed to warm to room temperature and stirred at roomtemperature for 1 hour. It was then refluxed overnight. After coolingthe reaction mixture to room temperature, it was poured slowly into 250mL of 3N HCl while the temperature was maintained below 15° C. Afterstirring for 30 minutes, the aqueous layer was extracted with methylenechloride (3×200 mL). The aqueous layer was adjusted to pH 6.8-6.9 byslow addition of concentrated NH₄OH at 15° C. and was extracted withmethylene chloride (3×100 mL). The aqueous layer was then evaporated todryness to give a colorless solid. This colorless solid was suspended in400 mL methylene chloride/methanol (7:3) and was stirred for 1 hour. Theinsolubles were filtered off, washed with methylene chloride/methanol(7:3). The filtrate was evaporated off to give colorless solid. 6.0 g ofthe colorless solid was chromatographed on silica gel. Elution withmethylene chloride/methanol (9:1→8.5:1.5) afforded the product as acolorless solid (1.5 g,). ¹H (DMSO, d₆):8.1 (br s, exchangeable, 1H),6.95 and 6.75 (q, 4H), 4.6 (m, exchangeable, 2H), 3.3 (m, 1H), 2.9 (m,2H), 1.2 (m, 10H); ¹³C (DMSO, d₆): 156.8, 130.5, 128.5, 115.2, 72.0,52.1, 48.6, 36.6, 33.6, 25.6, 21.7, 21.3. % Purity(HPLC): 97.4%.

5.6. EXAMPLE 6: Determination of Potency and Specificity

[0122] Several methods useful for the determination of the potency andspecificity of the compounds of this invention are disclosed in theliterature. See, e.g., Haskins, J. T. et al. Euro. J. Pharmacol.115:139-146 (1985). Methods that have been found particularly useful aredisclosed by Muth, E. A. et al. Biochem. Pharmacol. 35:4493-4497 (1986)and Muth, E. A. et al. Drug Develop. Res. 23:191-199 (1991), both ofwhich are incorporated herein by reference. 5.6.1 Receptor Binding

[0123] Determination of receptor binding of the compounds of thisinvention preferably is performed by the methods disclosed by Muth etal., and using the protocols summarized below in Table 1. TABLE IReceptor Binding Protocols Ligand Specific Incubation Molarity activityTemp. Receptor ³H-Ligand (nM) (Ci/mmol) Buffer Time (° C.) Displacingagent Dopamine-2 Spiperone 0.3 20-40 *^(a) 10 min 37° 1 mM (+)butaclamol Adrenergic WB 4101 0.5 15-30 50 mM 30 min 25° 10 mMnorepinephrine Tris-HCl bitartrate pH 7.7 Muscarinic Quinuclindinyl 0.06 30-60 50 mM 1 hr 25° 100 mM oxotremorine cholinergic benzilateTris-HCl pH 7.7 Histamine-1 Pyrilamine 2.0 <20 50 mM 30 min 25° 10 mMchlorpheniramine Phosphate maleate pH 7.5 Opiate Naloxone 1.3 40-60 50nM 30 min 0-4° 2 mM morphine Tris-HCl pH 7.4

[0124] The tissue homogenates used arc preferably whole brain exceptcerebellum (histamine-1 and opiate binding), cortex (α₁ adrenergicreceptor binding, monoamine uptake); and striatum (dopamine-2 andmuscarinic cholinergic receptor binding).

[0125] 5.6.2 Synaptosomal Uptake Studies

[0126] These studies may be performed using the modified methodology ofWood, M. D., and Wyllie, M. G. J. Neurochem. 37:795-797 (1981) asdescribed in Muth et al. Biochem. Pharmacol. 35:4493-4497 (1986).Briefly a P2 pellet is prepared from fresh rat brain tissue by sucrosedensity gradient centrifugation using a vertical rotor. For uptakestudies, all components are dissolved in the following buffer: 135 mMNaCl, 5 mM KCl, 1.2 mM MgCl₂, 2.5 mM CaCl₂, 10 mM glucose, 1 mM ascorbicacid, 20 mM Tris, pH 7.4, gassed with O₂ for 30 min prior to use.Various concentrations of test drug are preincubated with 0.1 μM[³H]dopamine or 0.1 μM [³H]norepinephrine (130,000 dpm/tube) and 0.1 μM[¹⁴C]serotonin (7,500 dpm/tube) in 0.9 ml buffer for 5 min at 37° C.One-tenth milliliter of synaptosomal preparation is added to each tubeand incubated for a further 4 min at 37° C. The reaction is thenterminated by the addition of 2.5 ml buffer, after which the mixture wasfiltered under vacuum using cellulose acetate filters (0.45 μM poresize). The filters are then counted in a scintillation counter, and theresults are expressed as pmoles uptake/mg protein/min. The IC₅₀ valuesfor uptake inhibition are calculated by linear regression of logit[percent of Na⁺-dependent uptake] vs. long [concentration of test drug].

[0127] 5.6.3. Reversal of Reserpine-Induced Hypothermia

[0128] Reversal of reserpine-induced hypothermia in male CF-1 mice(20-25 g., Charles River) may be performed according to an adaptation ofthe method of Askew, B. Life Sci. 1:725-730 (1963). Test compounds,suspended or solubilized in 0.25% Tween80® in water, are thenadministered i.p. at several dose levels to male mice (8/dose level) whohad been treated 18 hr previously with 45.0 mg/kg reserpine s.c. Avehicle control group is run simultaneously with drug groups. Testcompounds, vehicle, and reserpine are administered at a volume of 0.01ml/g. Reserpine is solubilized by the addition of a small amount(approximately 4 drops) of concentrated acetic acid and then brought tothe proper volume by the addition of distilled water. Rectaltemperatures are recorded by a Yellow Springs Instruments thermistorprobe at a dept of 2 cm. Measurements are taken 18 hr after reserpinepretreatment and at hourly intervals for 3 hr following administrationof either test compound or vehicle.

[0129] Rectal temperatures for all time periods are subjected to atwo-way analysis of variance for repeated measures with subsequentDunnett's comparison to control values to determine the minimumeffective dose (MED) for antagonizing reserpine-induced hypothermia.

[0130] 5.6.4. Induction of Rat Pineal Noradrenergic Subsensitivity

[0131] Suitable rats are male Sprague-Dawley rats (250-300 g, CharlesRiver) which should be maintained in continuous light throughout allexperiments so as to attenuate the diurnal fluctuation inbeta-adrenergic receptor density in the pineal gland and to maintain aconsistent supersensitive response to noradrenergic agonists. Moyer, J.A. et al. Soc. Neurosci. Abstract 10:261 (1984). After 2 days ofcontinuous light exposure, the rats are then injected twice daily witheither saline or test compound (10 mg/kg i.p.) for 5 days (total of 9injections). Another group of rats should receive saline injectionstwice daily for 4 days followed by a single injection of test compound(10 mg/kg i.p.) on the 5th day. One hour following the final injectionof test compound or saline, animals are administered either 0.1%ascorbic acid (controls), or isoproterenol (2 μmol/kg i.p. in 0.1%ascorbic acid). Rats are decapitated 2.5 minutes later, the time atwhich preliminary experiments have shown that the isoproterenol-inducedincreases in cyclic AMP levels in pineal glands are maximal. Moyer, J.A. et al. Mol. Pharmacol. 19:187-193 (1981). Pineal glands are removedand frozen on dry ice within 30 seconds to minimize anypost-decapitation increase in cAMP concentration.

[0132] Prior to radioimmunoassay for cAMP, the pineal glands are placedin 1 ml of ice-cold 2.5% perchloric acid and sonicated for approximately15 seconds. The sonicate is then centrifuged at 49.000 g for 15 min at4° C. and then resulting supernatant fluid is removed, neutralized withexcess CaCO₃, and centrifuged at 12,000 g for 10 min at 4° C. The cAMPcontent of the neutralized extract may be measured by a standardradioimmunoassay using ¹²⁵I-labeled antigen and antiserum (New EnglandNuclear Corp., Boston, Mass.). Steiner, A. L. et al. J. Biol. Chem.247:1106-1113 (1972). All unknown samples should be assayed in duplicateand compared to standard solutions of cAMP prepared in a 2.5% perchloricacid solution that had been neutralized with CaCO₃. Results areexpressed as pmol cAMP/pineal, and statistical analyses are performed byanalysis of variance with subsequent Student-Newman-Keuls tests.

[0133] 5.6.5. Single Unit Electrophysiology

[0134] The firing rates of individual neurons of the locus coeruleus(LC) or dorsal raphe nucleus (DR) in the chloral-hydrate anesthetizedrat are measured using single-barreled glass micro-electrodes aspreviously described for the LC. Haskins, J. T. et al. Eur. J.Pharmacol. 115:139-146 (1985). Using the stereotaxic orientation ofKonig, J. F. R., and Klippel, R. A. The rat brain: A stereotaxic atlasof the forebrain and lower parts of the brain stem Baltimore: Williamsand Wilkins (1963), the electrode tips should be lowered via a hydraulicmicrodrive from a point 1.00 mm above the locus coeruleus (AP 2.00 mmcaudal to the interaural line and 1.03 mm lateral to midline). Drugs areadministered i.v. through a lateral tail vein cannula. Only one cellshould be studied in each rat in order to avoid residual drug effects.

5.7. EXAMPLE 7: Oral Formulation

[0135] The pharmaceutical compositions of this invention may beadministered in a variety of ways. Oral formulations are of the easiestto administer.

[0136] 5.7.1. Hard Gelatin Capsule Dosage Forms

[0137] Table II provides the ingredients of suitable capsule forms ofthe pharmaceutical compositions of this invention. TABLE II Component 25mg capsule 50 mg capsule 100 mg capsule (−)-O-desmethyl- 25 50 100venlafaxine Microcrystalline 90.0 90.0 90.0 Cellulose Pre-gelatinized100.3 97.8 82.8 Starch Croscarmellose 7.0 7.0 7.0 Magnesium 0.2 0.2 0.2Stearate

[0138] The active ingredient (optically pure (−)-venlafaxine derivative)is sieved and blended with the excipients listed. The mixture is filledinto suitably sized two-piece hard gelatin capsules using suitablemachinery and methods well known in the art. See Remington'sPharmaceutical Sciences, 16th or 18th Editions, each incorporated hereinin its entirety by reference thereto. Other doses may be prepared byaltering the fill weight and, if necessary, by changing the capsule sizeto suit. Any of the stable hard gelatin capsule formulations above maybe formed.

[0139] 5.7.2. Compressed Tablet Dosage Forms

[0140] The ingredients of compressed tablet forms of the pharmaceuticalcompositions of the invention are provided in Table III. TABLE IIICompressed Tablet Unit Dosage Forms Component 25 mg capsule 50 mgcapsule 100 mg capsule (−)-O-desmethyl- 25 50 100 venlafaxineMicrocrystalline 90.0 90.0 90.0 Cellulose Pre-gelatinized 100.3 97.882.8 Starch Croscarmellose 7.0 7.0 7.0 Magnesium 0.2 0.2 0.2 Stearate

[0141] The active ingredient is sieved through a suitable sieve andblended with the excipients until a uniform blend is formed. The dryblend is screened and blended with the magnesium stearate. The resultingpowder blend is then compressed into tablets of desired shape and size.Tablets of other strengths may be prepared by altering the ratio of theactive ingredient to the excipient(s) or modifying the table weight.

[0142] While the invention has been described with respect to theparticular embodiments, it will be apparent to those skilled in the artthat various changes and modifications may be made without departingfrom the spirit and scope of the invention as defined in the claims.Such modifications are also intended to fall within the scope of theappended claims.

What is claimed is:
 1. A pharmaceutical composition which comprises(−)-venlafaxine derivative, or a pharmaceutically acceptable saltthereof, substantially free of its (+) stereoisomer and apharmaceutically acceptable carrier or excipient.
 2. The pharmaceuticalcomposition of claim 1 wherein the (−)-venlafaxine derivative isselected from the group consisting of (−)-O-desmethylvenlafaxine,(−)-N-desmethylvenlafaxine, (−)-N,O-didesmethylvenlafaxine, and(−)-N,N-didesmethylvenlafaxine.
 3. The pharmaceutical composition ofclaim 2 wherein the (−)-venlafaxine derivative is(−)-O-desmethylvenlafaxine or (−)-N,O-didesmethylvenlafaxine.
 4. Thepharmaceutical composition of claim 1 adapted for intravenous infusion,transdermal delivery, or oral delivery.
 5. The pharmaceuticalcomposition of claim 1 wherein the amount of (−)-venlafaxine derivative,or a pharmaceutically acceptable salt thereof, comprises greater thanabout 90% by weight of the total amount of racemic venlafaxinederivative.
 6. The pharmaceutical composition of claim 1 wherein the(−)-venlafaxine derivative comprises a hydrochloride salt thereof. 7.The pharmaceutical composition of claim 1 wherein said pharmaceuticallyacceptable excipient comprises lactose, croscarmellose sodium,microcrystalline cellulose, pre-gelatinized starch, and magnesiumstearate.
 8. The pharmaceutical composition of claim 1 wherein saidpharmaceutical composition is substantially free of all mono- ordi-saccharides.
 9. The pharmaceutical composition of claim 8 whereinsaid pharmaceutical composition is lactose-free.
 10. The pharmaceuticalcomposition of claim 1 wherein the (−)-venlafaxine derivative is(−)-O-desmethylvenlafaxine and the excipient comprises lactose.
 11. Thepharmaceutical composition of claim 10 wherein the excipient furthercomprises microcrystalline cellulose, pre-gelatinized starch, magnesiumstearate, and croscarmellose sodium.
 12. A pharmaceutical dosage formwhich comprises a therapeutically effective amount of (−)-venlafaxinederivative or a pharmaceutically acceptable salt thereof, substantiallyfree of its (+) stereoisomer, and a pharmaceutically acceptable carrieror excipient.
 13. The dosage form of claim 12 wherein said dosage formis a tablet or a capsule.
 14. The dosage form of claim 12 adapted forintravenous infusion, transdermal delivery, or oral delivery.
 15. Thedosage form of claim 14 wherein the therapeutically effective amount isfrom about 10 mg to about 1000 mg.
 16. The dosage form of claim 15wherein the therapeutically effective amount is from about 50 mg toabout 500 mg.
 17. The dosage form of claim 16 wherein thetherapeutically effective amount is from about 75 mg to about 350 mg.18. A method of preparing (−)-N-desmethylvenlafaxine which comprisescontacting a compound of Formula 5:

with a reductant for a time and at a temperature sufficient to form(±)-N-desmethylvenlafaxine, and isolating (−)-N-desmethylvenlafaxinetherefrom.
 19. The method of claim 18 wherein the reductant is BH₃.Me₂S.20. A method of preparing (−)-N,N-didesmethylvenlafaxine which comprisescontacting a compound of Formula 2:

with a reductant for a time and at a temperature sufficient to form(+)-N,N-didesmethylvenlafaxine, and isolating(−)-N,N-didesmethylvenlafaxine therefrom.
 21. The method of claim 20wherein the reductant is CoCl₂/NaBH₄.
 22. A method of preparing(−)-O-desmethylvenlafaxine which comprises contacting (+)-venlafaxinewith lithium diphenylphosphide for a time and at a temperaturesufficient to form (±)-O-desmethylvenlafaxine, and isolating(−)-O-desmethylvenlafaxine therefrom.
 23. Substantially pure(−)-O-desmethylvenlafaxine and pharmaceutically acceptable salts,solvates, and clathrates thereof.
 24. Substantially pure(−)-N,O-didesmethylvenlafaxine and pharmaceutically acceptable salts,solvates, and clathrates thereof.
 25. (−)-N-desmethylvenlafaxine andpharmaceutically acceptable salts, solvates, and clathrates thereof. 26.(−)-N,N-didesmethylvenlafaxine and pharmaceutically acceptable salts,solvates, and clathrates thereof.
 27. A method of treating an affectivedisorder in a human which comprises administering to a human in need ofsuch therapy a therapeutically effective amount of a (−)-venlafaxinederivative, or a pharmaceutically acceptable salt thereof, substantiallyfree of its (+) stereoisomer.
 28. The method of treating an affectivedisorder in a human according to claim 27 in which said amount of(−)-venlafaxine derivative, or a pharmaceutically acceptable saltthereof, substantially free of its (+) stereoisomer, is sufficient toalleviate the affective disorder but insufficient to cause adverseeffects associated with the administration of racemic venlafaxine. 29.The method of claim 27 wherein the affective disorder is selected fromthe group consisting of depression, attention deficit disorder, andattention deficit disorder with hyperactivity.
 30. A method for treatingobesity or weight gain in a human which comprises administering to ahuman in need of a reduction or maintenance in weight, a therapeuticallyeffective amount of a (−)-venlafaxine derivative, or a pharmaceuticallyacceptable salt thereof, substantially free of its (+) stereoisomer,said amount being sufficient to alleviate obesity or weight gain. 31.The method for treating obesity or weight gain in a human according toclaim 30 wherein said amount is sufficient to alleviate obesity orweight gain but insufficient to cause the adverse effects associatedwith administration of racemic venlafaxine.
 32. A method of treatingdisorders ameliorated by inhibition of neuronal monoamine reuptake in ahuman which comprises administering to a human in need of such therapy atherapeutically effective amount of a (−)-venlafaxine derivative, or apharmaceutically acceptable salt thereof, substantially free of its (+)stereoisomer, said amount being sufficient to alleviate said disorders.33. The method of treating disorders ameliorated by inhibition ofneuronal monoamine reuptake in a human according to claim 32 in whichsaid amount is sufficient to alleviate said disorders but insufficientto cause adverse effects associated with administration of racemicvenlafaxine.
 34. The method of treating disorders ameliorated byinhibition of neuronal monoamine reuptake in a human according to claim33 wherein said monoamine is dopamine.
 35. The method of treatingdisorders ameliorated by inhibition of neuronal monoamine reuptake in ahuman according to claim 33 wherein said disorder is Parkinson's diseaseor epilepsy.
 36. A method for treating cerebral function disorders inhumans which comprises administering to a human or therapeuticallyeffective amount of a (−)-venlafaxine derivative, or a pharmaceuticallyacceptable salt thereof, substantially free of its (+) stereoisomer,said amount being sufficient to alleviate cerebral function disorders.37. The method for treating cerebral function disorders in a humanaccording to claim 36 wherein said amount of a (−)-venlafaxinederivative, or a pharmaceutically acceptable thereof, substantially freeof its (+) stereoisomer, is sufficient to alleviate cerebral functiondisorders but insufficient to cause adverse effects associated withadministration of racemic venlafaxine.
 38. The method for treatingcerebral function disorders in a human according to claim 36 whereinsaid disorder is caused by a cerebrovascular disease.
 39. The method fortreating cerebral function disorders in a human according to claim 38wherein said cerebrovascular disease is selected from the groupconsisting of cerebral infarction, cerebral bleeding, cerebralarteriosclerosis, cerebral venous thrombosis and head injuries.
 40. Themethod for treating cerebral function disorders in a human according toclaim 38 wherein said cerebral function disorder is selected from thegroup consisting of senile dementia, Alzheimer's type dementia, memoryloss and amnesia/amnestic syndrome.
 41. A method for treating pain inhumans which comprises administering to a human a therapeuticallyeffective amount of a (−)-venlafaxine derivative, or a pharmaceuticallyacceptable salt thereof, substantially free of its (+) stereoisomer,said amount being sufficient to alleviate pain.
 42. The method fortreating pain in a human according to claim 41 wherein said amount of(−)-venlafaxine derivative, or a pharmaceutically acceptable thereof,substantially free of its (+) stereoisomer, is sufficient to alleviatepain but insufficient to cause adverse effects associated withadministration of racemic venlafaxine.
 43. The method for treating painin a human according to claim 41 wherein the pain is chronic pain.
 44. Amethod of treating an obsessive-compulsive disorder in a human, whichcomprises administering to a human in need of such therapy atherapeutically effective amount of a (−)-venlafaxine derivative, or apharmaceutically acceptable salt thereof, substantially free of its (+)stereoisomer.
 45. A method of treating substance abuse in a human, whichcomprises administering to a human in need of such therapy atherapeutically effective amount of a (−)-venlafaxine derivative, or apharmaceutically acceptable salt thereof, substantially free of its (+)stereoisomer.
 46. A method of treating or preventing pre-menstrualsyndrome in a human, which comprises administering to a human in need ofsuch therapy a therapeutically effective amount of a (−)-venlafaxinederivative, or a pharmaceutically acceptable salt thereof, substantiallyfree of its (+) stereoisomer.
 47. A method of treating anxiety in ahuman, which comprises administering to a human in need of such therapya therapeutically effective amount of a (−)-venlafaxine derivative, or apharmaceutically acceptable salt thereof, substantially free of its (+)stereoisomer.
 48. A method of treating an eating disorder in a human,which comprises administering to a human in need of such therapy atherapeutically effective amount of a (−)-venlafaxine derivative, or apharmaceutically acceptable salt thereof, substantially free of its (+)stereoisomer.
 49. A method of treating or preventing migraine, ormigraine headaches, in a human, which comprises administering to a humanin need of such therapy a therapeutically effective amount of a(−)-venlafaxine derivative, or a pharmaceutically acceptable saltthereof, substantially free of its (+) stereoisomer.
 50. A method fortreating or preventing incontinence in a human which comprisesadministering to a human in need of such therapy, a therapeuticallyeffective amount of a (−)-venlafaxine derivative, or a pharmaceuticallyacceptable salt thereof substantially free of its (+) stereoisomer. 51.The method of claim 50 wherein said incontinence is selected from thegroup consisting fecal incontinence, overflow incontinence, passiveincontinence, reflex incontinence, stress urinary incontinence, urgeincontinence, urinary exertional incontinence, and incontinence ofurine.
 52. The method of claim 27 wherein the (−)-venlafaxine derivativeis selected from the group consisting of (−)-O-desmethylvenlafaxine,(−)-N-desmethylvenlafaxine, (−)-N,O-didesmethylvenlafaxine, and(−)-N,N-didesmethylvenlafaxine.
 53. The method of claim 52 wherein the(−)-venlafaxine derivative is (−)-O-desmethylvenlafaxine or(−)-N,O-didesmethylvenlafaxine.
 54. The method of claim 27 wherein(−)-venlafaxine derivative is administered by intravenous infusion,transdermal delivery, or orally as a tablet or a capsule.
 55. The methodof claim 27 wherein the amount administered is from about 10 mg to about1000 mg per day.
 56. The method of claim 55 wherein the amountadministered is from about 50 mg to about 500 mg per day.
 57. The methodof claim 56 wherein the amount administered is from about 75 mg to about350 mg per day.
 58. The method of claim 27 wherein the amount of(−)-venlafaxine derivative, or a pharmaceutically acceptable saltthereof, is greater than approximately 90% by weight of the total amountof racemic venlafaxine derivative.
 59. The method of claim 27 whereinthe (−)-venlafaxine derivative, or a pharmaceutically acceptable saltthereof, substantially free of its (+) stereoisomer, is administeredtogether with a pharmaceutically acceptable carrier.
 60. The method ofclaim 27 wherein the (−)-venlafaxine derivative is administered as ahydrochloride salt.